Nerve growth factor (NGF) was the first neurotrophin to be identified, and its role in the development and survival of both peripheral and central neurons has been well characterized. NGF has been shown to be a critical survival and maintenance factor in the development of peripheral sympathetic and embryonic sensory neurons and of basal forebrain cholinergic neurons (Smeyne, et al., Nature 368:246–249 (1994); Crowley, et al., Cell 76:1001–1011 (1994)). NGF upregulates expression of neuropeptides in sensory neurons (Lindsay, et al., Nature 337:362–364 (1989)), and its activity is mediated through two different membrane-bound receptors, the TrkA tyrosine kinase receptor and the p75 receptor which is structurally related to other members of the tumor necrosis factor receptor family (Chao, et al., Science 232:518–521 (1986)).
In addition to its effects in the nervous system, NGF has been increasingly implicated in processes outside of the nervous system. For example, NGF has been shown to enhance vascular permeability in the rat (Otten, et al., Eur J Pharmacol. 106:199–201 (1984)), enhance T- and B-cell immune responses (Otten, et al., Proc. Natl. Acad. Sci. USA 86:10059–10063 (1989)), induce lymphocyte differentiation and mast cell proliferation and cause the release of soluble biological signals from mast cells (Matsuda, et al., Proc. Natl. Acad. Sci. USA 85:6508–6512 (1988); Pearce, et al., J. Physiol. 372:379–393 (1986); Bischoff, et al., Blood 79:2662–2669 (1992); Horigome, et al., J. Biol. Chem. 268:14881–14887(1993)). Although exogenously added NGF has been shown to be capable of having all of these effects, it is important to note that it has only rarely been shown that endogenous NGF is important in any of these processes in vivo (Torcia, et al., Cell. 85(3):345–56 (1996)). Therefore, it is not clear what the effect might be, if any, of inhibiting the bioactivity of endogenous NGF.
NGF is produced by a number of cell types including mast cells (Leon, et al., Proc. Natl. Acad. Sci. USA 91:3739–3743 (1994)), B-lymphocytes (Torcia, et al., Cell 85:345–356 (1996), keratinocytes (Di Marco, et al., J. Biol. Chem. 268:22838–22846)), smooth muscle cells (Ueyama, et al., J. Hypertens. 11:1061–1065 (1993)), fibroblasts (Lindholm, et al., Eur. J. Neurosci. 2:795–801 (1990)), bronchial epithelial cells (Kassel, et al., Clin, Exp. Allergy 31:1432–40 (2001)), renal mesangial cells (Steiner, et al., Am. J. Physiol. 261:F792–798 (1991)) and skeletal muscle myotubes (Schwartz, et al., J Photochem, Photobiol. B 66:195–200 (2002)). NGF receptors have been found on a variety of cell types outside of the nervous system. For example, TrkA has been found on human monocytes, T- and B-lymphocytes and mast cells.
An association between increased NGF levels and a variety of inflammatory conditions has been observed in human patients as well as in several animal models. These include systemic lupus erythematosus (Bracci-Laudiero, et al., Neuroreport 4:563–565 (1993)), multiple sclerosis (Bracci-Laudiero, et al., Neurosci. Lett. 147:9–12 (1992)), psoriasis (Raychaudhuri, et al., Acta Derm. l'enereol. 78:84–86 (1998)), arthritis (Falcimi, et al., Ann. Rheum. Dis. 55:745–748 (1996)), interstitial cystitis (Okragly, et al., J. Urology 161:438–441 (1991)), asthma (Braun, et al., Eur. J Immunol. 28:3240–3251 (1998)), pancreatits, and prostatitis.
Consistently, an elevated level of NGF in peripheral tissues is associated with inflammation and has been observed in a number of forms of arthritis. The synovium of patients affected by rheumatoid arthritis expresses high levels of NGF while in non-inflamed synovium NGF has been reported to be undetectable (Aloe, et al., Arch. Rheum. 35:351–355 (1992)). Similar results were seen in rats with experimentally induced rheumatoid arthritis (Aloe, et al., Clin. Exp. Rheumatol. 10:203–204 (1992); Halliday et al., Neurochem. Res. 23:919–22 (1998)). Elevated levels of NGF have been reported in transgenic arthritic mice along with an increase in the number of mast cells. (Aloe, et al., Int. J. Tissue Reactions-Exp. Clin. Aspects 15:139–143 (1993)).
Treatment with exogenous NGF leads to an increase in pain and pain sensitivity. This is illustrated by the fact that injection of NGF leads to a significant increase in pain and pain sensitivity in both animal models (Lewin et al., J. Neurosci. 13:2136–2148 (1993); Amann, et al., Pain 64, 323–329 (1996); Andreev, et al., Pain 63, 109–115 (1995)) and human (Dyck, et al., Neurology 48, 501–505 (1997); Petty, et al., Annals Neurol. 36, 244–246 (1994)). NGF appears to act by multiple mechanisms including inducing the neurotrophin BDNF (Apfel, et al., Mol. Cell. Neurosci. 7(2), 134–142 (1996); Michael, et al., J. Neurosci 17, 8476–8490 (1997)) which in turn changes pain signal processing in the spinal cord (Hains, et al., Neurosci Lett. 320(3), 125–8 (2002); Miletic, et al., Neurosci Lett. 319(3), 137–40 (2002); Thompson, et al., Proc Natl Acad Sci USA 96(14), 7714–8 (1999)), inducing changes in the peripheral and central connections of the sensory neurons and other pain-transmitting neurons in the spinal cord (Lewin, et al., European Journal of Neuroscience 6, 1903–1912 (1994); Thompson, et al., Pain 62, 219–231 (1995)), inducing changes in axonal growth (Lindsay, R M, J Neurosci. 8(7), 2394–405 (1988)) inducing bradykinin receptor expression (Peterson et al., Neuroscience 83:161–168 (1998)), inducing changes in expression of genes responsible for nerve activation and conduction such as ion channels (Boettger, et al., Brain 125(Pt 2), 252–63 (2002); Kerr, et al., Neuroreport 12(14), 3077–8 (2001); Gould, et al., Brain Res 854(1–2), 19–29 (2000); Fjell et al., J. Neurophysiol. 81:803–810 (1999)), potentiating the pain related receptor TRPV1 (Chuang, et al., Nature 411 (6840), 957–62 (2001); Shu and Mendell, Neurosci. Lett. 274:159–162 (1999)) and causing pathological changes in muscles (Foster, et al., J Pathol 197(2), 245–55 (2002)). Many of these changes take place directly on the pain transmitting sensory neurons and apparently are not dependent on concomitant inflammation. In addition, there are at least two other cell types known to respond to NGF and that may be involved in changes of pain sensation or sensitivity. The first of these, the mast cell, has been reported to respond to NGF with degranulation (Yan, et al., Clin. Sci. (Lond) 80:565–569 (1991)) or, in other studies, to cause or increase mediator production or release in collaboration with other agents (Pearce and Thompson, J. Physiol. 372:379–393 (1986), Kawamoto, et al., J. Immunol. 168:6412–6419 (2002)). It has clearly been shown in the rat that NGF mediated pain responses are at least somewhat mediated by mast cells (Lewin, et al., Eur. J. Neurosci. 6:1903–1912 (1994), Woolf, et al., J. Neurosci. 16:2716–2723 (1996) although the potential relevance of this remains to be shown in humans. Primary sympathetic neurons are also known to respond to NGF and to also be involved in pain signaling (Aley, et al., Neuroscience 71:1083–1090 (1996)). It is clear that removing sympathetic innervation modifies the hyperalgesia normally seen in response to treatment with NGF (Woolf, et al., J. Neurosci. 16:2716–2723 (1996)).
The use of NGF antagonists, such as anti-NGF antibody, to treat various types of pain, has been described. See, e.g., U.S. Ser. Nos. 10/682,331, 10/682,638, 10/682,332 (Pub. No. 2004/0131615), Ser. No. 10/783,730 (Pub. No. 2004/0253244), Ser. No. 10/745,775 (Pub. No. 2004/0237124), Ser. No. 10/791,162; PCT/US03/32089 (WO 04/032870); PCT/US03/32083 (WO 2005/000194); PCT/US03/32113; PCT/US2004/05162 (WO 04/073653); PCT/US03/41252 (WO 04/058184).
Bone cancer pain may arise in humans from either primary bone tumors or more commonly from bone metastases (such as from breast, prostate, and lung carcinomas). See Luger et al., Pain 99:397–406 (2002). A mouse model of bone cancer pain has been developed, and this model of bone cancer pain mirrors the pain observed in humans with moderate to advanced bone cancer pain. See Luger et al., Pain 99:397–406 (2002); Clohisy et al., Clinical Orthopaedics and Related Research 415S:S279–S288 (2003); Schwei et al., J. Neruosci. 19:10886–10897 (1999); Honore et al., Nat. Med. 6: 521–529 (2000). Papers by Honore et al. and Schwei et al. state that the neurochemical signature of observed changes in the spinal cord and DRG of bone cancer bearing animals is unique and distinguishable from either typical inflammatory pain or typical neuropathic pain although there seem to be components of this biochemical signature similar to classic inflammatory and neuropathic pain states in this model. Honore et al. Neuroscience 98:585–598 (2000); Schwei et al. J. Neruosci. 19:10886–10897 (1999); Luger et al., Pain 99:397–406 (2002).
All references cited herein, including patent applications and publications, are incorporated by reference in their entirety.